1. Field of the Invention
The present invention relates generally to medical devices and methods. More particularly, the present invention relates to methods and apparatus for inhibiting neointimal hyperplasia in arteries following angioplasty, stenting, or other intravascular procedures for treating atherosclerotic disease.
A number of percutaneous intravascular procedures have been developed for treating atherosclerotic disease in a patient""s vasculature. The most successful of these treatments is percutaneous transluminal angioplasty (PTA) which employs a catheter having an expansible distal end, usually in the form of an inflatable balloon, to dilate a stenotic region in the vasculature to restore adequate blood flow beyond the stenosis. Other procedures for opening stenotic regions include directional atherectomy, rotational atherectomy, laser angioplasty, stents and the like. While these procedures, particularly PTA followed by stenting, have gained wide acceptance, they continue to suffer from the subsequent occurrence of restenosis.
Restenosis refers to the re-narrowing of an artery within weeks or months following an initially successful angioplasty or other primary treatment. Restenosis afflicts up to 50% of all angioplasty patients and results at least in part from vascular smooth muscle cell proliferation in response to the injury caused by the primary treatment, generally referred to as xe2x80x9cneointimal hyperplasia.xe2x80x9d Blood vessels in which significant restenosis occurs will require further treatment.
A number of strategies have been proposed to reduce restenosis. Such strategies include prolonged balloon inflation, treatment of the blood vessel with a heated balloon, treatment of the blood vessel with ionizing radiation, the administration of anti-thrombotic drugs following the primary treatment, stenting of the region following the primary treatment, and the like. While enjoying different levels of success, no one of these procedures has proven to be entirely successful in treating all occurrences of restenosis.
Of particular interest to the present invention, the application of ionizing radiation from radioisotopes following angioplasty has shown great promise for the inhibition of hyperplasia. Despite its great promise, the use of intravascular radiation suffers from a number of proven and suspected deficiencies. Such ionizing radiation treatments do not appear to promote healing of the endothelial layer which forms over the neointimal layer, particularly over stented regions of a treated artery. The radiation may also be harmful to the medial region of the arterial wall, subjecting the patient to long-term risk. On a practical level, the need to handle and dispose of radioisotopes is problematic and presents some risk to both the patient and the individuals treating the patient. While the use of isotopes having a very short half-life reduces these problems somewhat, the fabrication and inventory maintenance of catheters and devices employing such isotopes is difficult because the very short shelf-life. It will be appreciated that the window of opportunity for using isotopes having a very short half-life is quite limited.
The use of ultrasound energy for treating restenosis on a blood vessel has been proposed in U.S. Pat. No. 5,836,896. In particular, that patent teaches that high amounts of ultrasonic energy can be delivered to a blood vessel in order to reduce the viability, migration, and adhesion of smooth muscle cells. The ultrasonic energy is delivered under conditions which cause cavitation within the smooth muscle cells. The preferred operational parameters are low frequency (15 kHz to 250 kHz) and high energy capable of causing the intended cavitation. In a particular example, use of a longitudinal vibration transmission wire to first recanalize an artery and subsequently radiate the vascular intima to inhibit smooth muscle cell migration, viability, and adherence is described. While positive results are reported, there are no controls to confirm whether the post-recanalization therapy was responsible for the observed patency.
For these reasons, it would be desirable to provide alternative methods and apparatus for the treatment of intimal hyperplasia in arteries following angioplasty, stenting, and other recanalization treatments. It would be particularly desirable to provide methods and apparatus for the application of vibrational energy to the arterial wall, where the energy would at least partly inhibit excessive cell proliferation of vascular smooth muscle cells in the neointimal layer which forms following a primary treatment and which can result in hyperplasia and subsequent restenosis of the blood vessel. It would be even more desirable if the energy source were generated in situ within the blood vessel and were of a type which may be readily turned on and turned off without exposing the patient and treating personnel to significant risk. The apparatus intended for performing the method should be suitable for vascular introduction, preferably via percutaneous intravascular access. In addition, it would be desirable to provide methods for inhibiting the hyper-proliferation of vascular smooth muscle cells in the neointimal layer following arterial injury without substantially diminishing the viability or migration capability of the cells. It would be still further desirable to provide for ultrasonic and other vibrational therapy for the inhibition of neointimal hyperplasia without inducing substantial cavitation or creating substantial heating in the arterial wall being treated. Such treatments would desirably promote healing and re-endothelialization of the arterial wall. At least some of these objectives will be met by the invention described hereinafter.
2. Description of the Background Art
Intravascular inhibition of hyperplasia by exposure to radioisotopes is described in a number of patents and publications, including U.S. Pat. Nos. 5,616,114; 5,302,168; 5,199,939; and 5,059,166. The therapeutic application of ultrasonic energy is described in a number of patents and publications including U.S. Pat. Nos. 5,362,309; 5,318,014; 5,315,998, WO 98/48711; and others.
The application of intravascular ultrasound for inhibiting restenosis by decreasing the migration, viability, and adhesion of vascular smooth muscle cells via a cavitation mechanism is suggested in U.S. Pat. No. 5,836,896. Vascular smooth muscle cell migration, however, has been shown not to contribute significantly to neointimal thickening after arterial injury. See, Bendeck et al. (1996) Circ. Res. 78:38-43. Vascular smooth muscle cell proliferation, migration, and adhesion have been shown to decrease in cell culture in response to ultrasonically induced cavitation. Alter et al. (1998) 24:711-721. See also Rosenchein et al. (1990) JACC 15:711-717 and Siegel et al. (1991) J. Invasive Cardiol. 3:135 which describe thrombolysis via the cavitation mechanism.
A high frequency ultrasonic catheter intended for tissue ablation which employs an air-backed transducer is described in He et al. (1995) Eur. Heart J. 16:961-966. Cell lysis of mammalian cell lines maintained in vitro is described in Kaufman et al. (1977) Ultrasound Med. Biol. 3:21-25. Catheters suitable for performing at least some methods according to the present invention are described in co-pending application Ser. Nos. 08/565,575; 08/566,740; 08/566,739; 08/708,589; 08/867,007, and 09/223,225, and assigned to the assignee of the present invention, the full disclosures of which are incorporated herein by reference.
The present invention provides for treatment of a target site within a coronary artery or other blood vessel subject to occlusion from neointimal hyperplasia. By xe2x80x9cneointimal hyperplasia,xe2x80x9d it is meant that excessive cell proliferation occurs at the target site within the blood vessel, usually resulting from treatment of a primary occlusion by angioplasty, atherectomy, stenting, or other conventional intravascular treatment for widening or de-bulking the primary occlusion. It has been found that such primary treatments often damage the cells lining the blood vessel in a manner which results in an injury response characterized by secretion of extracellular matrix and excessive proliferation of the smooth muscle cells lining the blood vessel which together make up the neointimal layer lining the arterial wall.
Treatment according to the present invention is effected by exposing a target site within the arteries at risk of hyperplasia to vibrational energy at a mechanical index and for a time sufficient to inhibit hyperplasia of smooth muscle cells within the neointimal layer of the arterial wall. Surprisingly, it has been found that the strength of vibrational energy (as measured by the mechanical index) and the duration of the treatment (as measured by elapsed treatment time, duty cycle, and pulse repetition frequency (PRF)) can be selected to provide highly effective hyperplasia inhibition in the neointimal layer without significant damage to surrounding tissues or structures within the artery. In particular, by exposing an arterial target site at risk of neointimal hyperplasia to a vibrational energy having a mechanical index in the range from 0.1 to 50, preferably from 0.2 to 10, and more preferably from 0.5 to 5, for a treatment time in the range from 10 seconds to 1000 seconds, preferably from 30 seconds to 500 seconds, and more preferably from 60 seconds to 300 seconds, the proliferation of vascular smooth muscle cells in the neointimal layer of the artery can be reduced by at least 2% (in comparison with untreated controls) after seven days, often at least 4%, and sometimes 6% or greater. The resulting reduction in hyperplasia mass after 28 days will typically be at least 10%, usually at least 20%, and preferably at least 30%. Such inhibitions can be achieved without significant necrosis of the smooth muscle cells. Prior methods of hyperplasia inhibition which rely on necrosis present a substantial risk of injuring not only the neointimal layer (which can prevent rapid and/or normal healing of the layer) but also the medial layer and other arterial tissues and structures. The methods of the present invention will preferably be performed under conditions which cause little or no cavitation within the smooth muscle cells and other cells within or near the treatment region. While the initiation of cavitation will be governed to a large extent by the power and mechanical index off the vibrational energy, the presence of cavitation nucleii, such as gas microbubbles, can also contribute to cavitation. Thus, the methods of the present invention will preferable be performed in the absence of introduced microbubbles and/or other cavitation nucleii. Moreover, the treatment conditions of the present invention will result in little or no inhibition of migration of smooth muscle cells into the neointimal layer. Instead, the migration will be generally normal, but the migrated cells will have a quiescent phenotype rather than the proliferative phenotype associated with the formation of neointimal hyperplasia. In their proliferative phenotype, vascular smooth muscle cells not only divide rapidly but also excrete extracellular matrix which accounts for most of the volume of the neointimal layer responsible for hyperplasia. Quiescent smooth muscle cells divide less rapidly, do not secrete significant amounts of extracellular matrix, and promote healing and reformation of an intact endothelial layer over the neointimal layer. Additionally, the duty cycles and pulse repetition frequencies of the treatment will be selected to limit the heating within the neointimal layer to a temperature rise below 10xc2x0 C., preferably below 5xc2x0 C., and more preferably below 2xc2x0 C. Such limited temperature rise further assures the viability and normalcy of the treated cells to enhance healing and re-endothelialization of the neointimal layer in a rapid manner.
Thus, the present invention can provide a number of related treatments and therapies. In a broad sense, the methods of the present invention can be used to treat virtually any arterial injury at risk of hyperplasia to both limit the extent of neointimal hyperplasia and promote the rapid and complete healing of an endothelial layer over the neointimal layer. Additionally, the methods of the present invention can be performed as part of a treatment method for stenotic arterial disease, where the vibrational energy will be employed in conjunction with a primary recanalization technique, typically balloon angioplasty, atherectomy, laser angioplasty, and the like. In such treatments, the vibrational energy may be applied sequentially, concurrently, or both sequentially and concurrently. For example, in the case of balloon angioplasty, a vibrational transducer could be located within the angioplasty balloon to apply vibrational energy both during and after the arterial dilatation. Additionally, the present invention will find particular use in conjunction with stent placement. The use of stents is itself a secondary treatment to inhibit restenosis following angioplasty or other primary recanalization treatments. While stents are very effective in preventing abrupt reclosure and late negative remodeling, they are generally much less effective in preventing neointimal hyperplasia. Indeed, the placement of a stent following angioplasty can in at least some instances promote neointimal hyperplasia when compared to angioplasty alone. Thus, by applying vibrational energy according to the methods of the present invention either before or shortly after stent placement, the long-term patency of stents can be greatly improved. Moreover, it may be desirable in some instances to select both the frequency of the vibratory energy and the resonance properties of the stent so that the stent may be driven in at its resonant frequency to enhance and/or distribute the vibratory energy to the arterial wall in a manner which is superior to the delivery of vibratory energy.
Mechanical index and duration of the treatment are the most important treatment perimeters. The mechanical index (MI) is a function of both the intensity and the frequency of the vibrational energy produced, and is defined as the peak rarefactional pressure (P) expressed in megaPascals divided by the square root of frequency (f) expressed in megaHertz:   MI  =      P          f      
The duration of treatment is defined as the actual time during which vibrational energy is being applied to the arterial wall. Duration will thus be a function of the total elapsed treatment time, i.e., the difference in seconds between the initiation and termination of treatment; burst length, i.e., the length of time for a single burst of vibrational energy; and pulse repetition frequency (PRF). Usually, the vibrational energy will be applied in short bursts of high intensity (power) interspersed in relatively long periods of no excitation or energy output. An advantage of the spacing of short energy bursts is that heat may be dissipated and operating temperature reduced.
Broad, preferred, and exemplary values for each of these perimeters is set forth in the following table.
The vibrational energy will usually be ultrasonic energy applied intravascularly using an intravascular catheter having an interface surface thereon, usually near its distal end. The catheter will be intravascularly introduced so that the interface surface lies proximate the target region to be treated.
Preferably, the ultrasonic or other vibrational energy will be directed radially outward from an interface surface into a target site or region within the arterial wall. By xe2x80x9cradially outward,xe2x80x9d it is meant that the compression wave fronts of the vibrational energy will travel in a radially outward direction so that they enter into the arterial wall in a generally normal or perpendicular fashion. It will generally not be preferred to direct the vibrational energy in a direction so that any substantial portion of the energy has an axial component.
In most instances, it will be desirable that the vibrational energy be distributed over an entire peripheral portion or section of the arterial wall. Such peripheral portions will usually be tubular having a generally circular cross-section (defined by the geometry of the arterial wall after angioplasty, stenting, or other recanalization treatment) and a length which covers at least the length of the treated arterial wall. While it may be most preferred to distribute the vibrational energy in a peripherally and longitudinally uniform manner, it is presently believed that complete uniformity is not needed. In particular, it is believed that a non-uniform peripheral distribution of energy over the circumference of the arterial wall will find use, at least so long as at least most portion of walls are being treated.
Even when vibratory forces are spaced-apart peripherally and/or longitudinally, the effective distribution of vibrational energy will be evened out by radiation pressure forces arising from the absorption and reflection of ultrasound on the circumferential walls of the arterial lumen, thereby producing a uniform effect due to the fact that the tension in the wall of the lumen will tend to be equal around its circumference. Accordingly, a uniform inhibitory effect can occur even if there is some variation in the intensity of the ultrasound (as in the case of the non-isotropic devices described hereinafter). This is due to the fact that the tension around the circumference of the lumen will be equal in the absence of tangential forces.
Usually, the interface surface will be energized directly or indirectly by an ultrasonic transducer which is also located at or near the distal tip of the catheter. By direct, it is meant that the surface is part of the transducer. By indirect, it is meant that the transducer is coupled to the surface through a linkage, such as a resonant linkage as described hereinafter. Alternatively, energy transmission elements may be provided to transfer ultrasonic energy generated externally to the catheter to the interface surface near its distal tip. As a further alternative, although generally less preferably, the ultrasonic energy may be generated externally and transmitted to the target region by focusing through the patient""s skin i.e., without the use of a catheter or other percutaneously introduced device. Such techniques are generally referred to as high intensity focused ultrasound (HIFU) and are well described in the patent and medical literature.
When employing an intravascularly positioned interface surface, the surface may directly contact all or a portion of the blood vessel wall within the target region in order to effect direct transmission of the ultrasonic energy into the wall. Alternatively, the interface surface may be radially spaced-apart from the blood vessel wall, wherein the ultrasonic energy is transmitted through a liquid medium disposed between the interface surface and the wall. In some cases, the liquid medium will be blood, e.g., where the interface surface is within an expansible cage or other centering structure that permits blood flow therethrough. In other cases, the liquid medium may be another fluid either contained within a balloon which circumscribes the transducer and/or contained between axially spaced-apart balloons which retain the alternative fluid. Suitable ultrasonically conductive fluids include saline, contrast medium, and the like. In some cases, the medium surrounding the interface surface will include drugs, nucleic acids, or other substances which are intended to be intramurally delivered to the blood vessel wall. In particular, the delivery of nucleic acids using intravascular catheters while simultaneously directly inhibiting cell proliferation and hyperplasia is described in co-pending application Ser. No. 60/070,073, assigned to the assignee of the present application, filed on the same day as the present application, the full disclosure of which is incorporated herein by reference.
Ultrasonic or other vibrational excitation of the interface surface may be accomplished in a variety of conventional ways. The interface surface may be an exposed surface of a piezoelectric, magnetostrictive, or other transducer which is exposed directly to the environment surrounding the catheter. Alternatively, the transducer may be mechanically linked or fluidly coupled to a separate surface which is driven by the transducer, optionally via a resonant linkage, as described in co-pending application Ser. Nos. 08/565,575; 08/566,740; 08/566,739; 08/708,589, 08/867,007; and 09/223,225, the full disclosures of which have previously been incorporated herein by reference. Preferably, the interface surface may be vibrated in a generally radial direction in order to emit radial waves into the surrounding fluid and/or directly into the tissue. Alternatively, the interface surface may be vibrated in a substantially axial direction in which case axial waves may be transmitted into the surrounding environment and/or directly into the blood vessel wall.
The methods of the present invention may further comprise the primary treatment of an occlusion within a blood vessel in order to widen or recanalize the blood vessel. Suitable primary treatments include angioplasty, atherectomy, stenting, laser angioplasty, thermal angioplasty, and the like. Following the primary treatment, the treated region may be exposed to ultrasonic vibrational energy as generally described above.
Usually, however, it will be desirable to place a stent within the recanalized region as a further part of the present invention. The vibrational energy may be applied before implantation of the stent, during implantation of the stent, or following stent implantation.
The present invention further provides improved methods of the type where intravascular hyperplasia is inhibited by the application of energy, such as the application of radiation from radioisotopes, x-rays sources, or the like. The improvement herein comprises the application of ultrasonic energy to the blood vessel wall in place of the other energy sources.
The present invention still further comprises systems including a catheter having an interface surface and a power source connectable to the catheter. The power source will be adapted to energize the interface surface according to any of the methods set forth above.
The present invention still further comprises kits including a catheter having an interface surface. The kits further include instructions for use according to any of the methods set forth above. Optionally, the kits may still further include a conventional package, such as a pouch, tray, box, tube, or the like. The instructions may be provided on a separate printed sheet (a package insert setting forth the instructions for use), or may be printed in whole or in part on the packaging. A variety of other kit components, such as drugs to be delivered intravascularly through the catheter, could also be provided. Usually, at least some of the components of the system will be maintained in a sterile manner within the packaging.